Anorexigenic tetrahydrobenzazepines

ABSTRACT

7-CHLORO-2,3,4,5-TETRAHYDRO-1H-3-benzazepines and pharmaceutically acceptable acid addition salts thereof are prepared; therapeutical compositions containing said compounds and methods for producing an anorexigenic effect in a mammal are provided.

Unite States Patent 1 Hoegerle et al.

ANOREXIGENIC TETRAHYDROBENZAZEPINES Inventors: Karl Hoegerle, Basel;Ernst Habicht,

Oberwil, both of Switzerland Ciba-Geigy Corporation, Ardsley, N.Y.

Filed: March 11, 1970 Appl. No.: 23,523

Related US. Application Data Division of Ser. No. 751,381, Aug. 9, I968,abandoned, which is a continuation-in-part of Ser. No. 705,627, Feb. 15,I968, abandoned.

U.S. Cl ..424/244, 260/239 BB Int. Cl. ..A6lu 27/00 Field of Search..424/244; 260/239 BB References Cited UNITED STATES PATENTS 12/1969Tokolics et al. ..260/239 Assignee:

( 51 Feb.13,1973

4/ l 967 Koch ..260/239 FOREIGN PATENTS OR APPLICATIONS 1,473,840 2/l967France ..260/239 Primary ExaminerStanley J. Friedman Attorney-Karl F.Jorda and Bruce M. Collins thereof are prepared; therapeuticalcompositions containing said compounds and methods for producing ananorexigenic effect in a mammal are provided.

6 Claims, No Drawings Mull ..260/239 ANOREXIGENIC TETRAHYDROBENZAZEPINESCROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisionalof Ser. No. 75l,38l, filed Aug. 9, 1968, which, in turn, is acontinuation-inpart of Ser. No. 705,627, filed Feb. 15, 1968, both nowabandoned.

DETAILED DISCLOSURE wherein R is hydrogen or methyl, andpharmaceutically acceptable acid addition salts thereof.

The compounds of Formula I are produced by treating a phenyl-ethylaminederivative of Formula II wherein R is hydrogen or methyl and X ischloro, bromo, or iodo or an inorganic acid addition salt of such acompound with a Lewis acid at elevated temperatures, and isolating thereaction product of Formula I in a conventional manner.

Inorganic acid addition salts of the compounds of Formula II suitablefor the cyclization reaction are such as derived from, e.g. hydrochloricacid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid,preferably hydrochloric acid and hydrobromic acid.

Lewis acids which can be used in the process are, e.g.antimony-(V)-chloride, iron-(IIl)-chloride, tellurium- (ID-chloride,stannium-(IV)-chloride, titanium-(IV)- chloride,tellurium-(IV)-chloride, bismuth-(Ill)- chloride, zinc chloride and, inparticular, aluminum chloride, as well as the corresponding bromides oriodides. Other Lewis acids suitable for the cyclization process are,e.g., boron trifluoride or boron trichloride. Also sulfuric acid,phosphorous pentoxide or polyphosphoric acid can be used in the process;

The Lewis acid is usually employed in the reaction in an amount of fromabout 0.5 to mol equivalents preferably from about 1 to 1.5 molequivalents.

The reaction is carried out at elevated temperatures ranging from about100 to about 300. The preferred temperature range is from about 150 toabout 250.

Reaction time varies between about 5 and about 50 hours and ispreferably between about and about hours. The tetrahydro-benzazepineformed during the reaction is isolated by cooling the reaction mixtureand pouring it on ice. The free base is liberated by addition of astrong base, preferably an inorganic base, e.g., an alkali hydroxidesuch as sodium hydroxide, potassium hydroxide, or an alkaline earthoxide. The reaction of a phenylyalkylamine of Formula II and a Lewisacid can be carried out in the presence or absence of a solvent ordiluent. If the presence of a solvent is desired, an aliphatichydrocarbon such as heptane or cyclohexane, a nitrated hydrocarbon suchas nitromethane, nitrocyclohexane or nitrobenzene, a halogenatedhydrocarbon such as carbon tetrachloride, ethylene chloride, methylenechloride, o-dichlorobenzene, or also carbon disulfide can be used.

Starting materials of Formula II are obtained by addition of a hydrogenhalide, e.g., hydrogen chloride or hydrogen bromide in a known manner tothe aziridine derivatives of Formula III.

(III) wherein R is hydrogen or methyl.

The aziridine derivatives of Formula IlI can be obtained in analogy to amethod described in the British Patent Specification No. 692,360 and inanalogy to H. Bestian, Ann. 566, 238-239, by addition of ethylenimine top-chlorostyrene in the presence of an alkali metal, respectively top-chloro-B-methylstyrene.

Acid addition salts of the tetrahydrobenzazepin derivatives of Formula Iare prepared via conventional methods, e.g., by dissolving equimolaramounts of the free base and the acid in a suitable polar solvent, e.g.in water or a lower alkanol and evaporating the solvent, or bydissolving the free base in a suitable relatively unpolar solvent, e.g.in acetone, methyl ethyl ketone, diethyl ether, benzene, carbontetrachloride and the like and adding the acid or the solution of theacid in a similar or the same solvent, whereupon the acid addition saltprecipitates and can be isolated by filtration.

Acids used for the production of acid addition salts are, e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methane sulfonic acid, ethane sulfonic acid, B-hydroxyethane sulfonicacid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid,oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,salicylic acid, phenyl-acetic acid, mandelic acid and embonic acid.

7-chloro-2,3 ,4,5-tetrahydro- 1 H-B-benzazepine and2-methyl-7-chloro-2,3,4,5-tetrahydro-1H3- benzazepine and the acidaddition salts thereof have been found to have valuable pharmacologicalproperties, especially anorexigenic activity combined with a low orderof toxicity. These favorable properties render the compounds of theinvention well suited for the treatment of obesity.

The anorexigenic effects of the compounds of the invention areillustratively demonstrated according-to the method of Spengler andWaser, Helv. Physiol. Pharmac. Acta 15, 444-449 (1957) in rats trainedto consume food during day-time. Thus it is shown that 7- chloro-2,3,4,5-tetrahydrol H-3-benzazepine hydrochloride on oral administration inamounts of about 10 mg/kg inhibits food consumption to a verysignificant extent. The same compound administered intraperitoneally torats exhibits the same effect already in a dose of 5 mg/kg.

The acute toxicity of 7-chloro-2,3,4,5-tetrahydro-l l-l-3-benazepinehydrochloride as demonstrated in rats per us is of low order.

For their intended use the compounds of the inven tion are administeredorally, rectally or, particularly in the form of aqueous solutions ofthe acid addition salts, also parenterally, in amounts depending on thespecies, age and weight of the subject under treatment as well as on theparticular condition to be treated and the mode of administration.

Generally the daily dosages of the compounds of the invention varybetween 0.3 and 10 mg/kg of bodyweight on oral administration.

For administration purposes therapeutica] compositions are preparedcontaining a compound of Formula 1 and/or at least one pharmaceuticallyacceptable acid addition salt thereof, an inert pharmaceutical carrierand, if desired, other additives. These compositions are presented fororal, rectal or parenteral administration in dosage units such astablets, dragees, capsules, suppositories or ampoules, preferablycontaining as active ingredient 550 mg of an active substance accordingto the invention.

Dosage units for oral administration preferably contain between 1-90percent of the 7-chloro-2,3,4,5- tetrahydro-1H-3-benzazepines orpharmaceutically acceptable salts thereof as active substance. They maybe produced by combining the active substance with, e.g. solid,pulverulent carriers such as lactose, saccharose, sorbitol, mannitol;starches such as potato starch, maize starch or amylopectin, alsolaminaria powder or citrus pulp powder; cellulose derivatives orgelatine, optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols, to form tablets or drageecores. The latter are coated, eg with concentrated sugar solutions whichcan also contain, e.g. gum arabic, talcum and/or titanium dioxide,

or with a lacquer dissolved in easily volatile organic solvents ormixtures of solvents.

Dyestuffs can be added to these coatings, e.g. to distinguish betweenvarying dosages of active sub- 1 stance.

Other suitable dosage units for oral administration are hard gelatinecapsules and also soft closed capsules made of gelatine and a softenersuch as glycerin. The

hard gelatine capsules preferably contain the active substance as agranulate, e.g. in admixture with fillers such as maize starch and/orlubricants such as talcum or magnesium stearate and, optionally,stabilizers such as sodium metabisulfite (Na S O or ascorbic acid. Insoft capsules, the active substance is preferably dissolved or suspendedin suitable liquids such as liquid polyethylene glycols, to whichstabilizers can also be added.

Examples of dosage units for rectal administration are suppositorieswhich consist of a combination of the active substance or a suitablesalt thereof with a fatty foundation, or also 'gelatine rectal capsuleswhich contain a combination of the active substance or a suitable saltthereof with polyethylene glycols.

The following examples further illustrate the production of thecompounds of the invention and the starting material therefor, as wellas the production of therapeutic compositions containing these compoundsas active ingredients.

EXAMPLE 1 a. A mixture of g of finely pulverized N-(2-chloroethyl)-p-chloro-phenylethylamine hydrochloride and 133 g ofaluminum chloride is stirred and slowly heated up to a temperature ofabout 170180. This temperature is maintained for about 12 hourswhereupon the mixture is cooled to about 100 and poured on ice understirring. This solution is rendered alkaline by addition of about 2.5liters of 30 percent aqueous sodium hydroxide solution and extractedseveral times with ether. The combined ether solutions are dried overmagnesium sulfate and potassium carbonate, filtered, and evaporated invacuo. The residue is distilled at 0.1 mmHg to give7-chloro-2,3,4,5-tetrahydro-lH-3- benzazepine; bp 1 l0-l15/0.1 mml-lg; n1.5765.

The hydrochloride is prepared in conventional manner and isrecrystallized from acetonitrile; mp-

The starting material used in above reaction is produced according tothe following reaction sequence:

b. To a stirred mixture of 200 g of dry ethylenimine and 5 g of metallicsodium is added dropwise 138 g of freshly distilled4-chlorostyrene in away that the temperature of the reaction mixture does not exceed 40.After completion of the addition stirring is continued overnight at roomtemperature. Unreacted sodium is removed mechanically and the excessethylenimine is removed in vacuo. The residue is distilled andfractionated at 0.7 mm-Hg to give 1-( p-chloro-phenylethyl)-aziridine;bp 93/0.7 mmHg; n 1.5357.

c. Methanol (500ml) is stirred in an ice bath and saturated withhydrogen chloride. A solution of g of l-(p-chlorophenylethyl)-aziridinein 100 ml of methanol is added dropwise at a temperature of about 10 to15. The solution is evaporated to dryness. The residue is dried in vacuoat 60 and recrystallized from acetonitrile to give N-(2-chloroethyl)-p-chloro-phenylethylamine hydrochloride; mp 18919l.

EXAMPLE 2 a. A mixture of 30 g of l-(p-chlorophenyl)-2-(2- Thehydrochloride is prepared in conventional manner and is recrystallizedfrom acetonitrile; mp 216-218".

The starting material used in above reaction is produced as follows:

b. To a solution of 56.3 g of chlorobenzene in 200 ml of carbondisulfide is added 150 g of aluminum chloride. The mixture is refluxedand 79 g of propionic acid anhydride is added whereupon reflux iscontinued for one hour. Carbon disulfide is distilled off, the residueis poured on 600 g of ice and 300 g of concentrated hydrochloric acidand the oil which separates is extracted with benzene. The combinedbenzene extracts are washed with water, sodium hydroxide solution andagain with water, dried over magnesium sulfate, filtered and evaporated.The residue is distilled to give p-chloropropio-phenone; bp 120/10 mmHg.

0. To a stirred mixture of 8.9 g of sodium borohydride and two pelletsof potassium hydroxide in 150 ml of methanol is added at about 15-20within 30 minutes a solution of 57 g of p-chloropropiophenone. Themixture is stirred for 2 hours at 2530 and kept at room temperatureovernight whereupon 125 ml of 2N hydrochloric acid is added. The acidicmixture is evaporated and the residue extracted with benzene. Thebenzene layer is dried over sodium sulfate and evaporated. The residueis distilled to give l-(pchlorophenyl)-propanol; bp 128130/13 mmHg; n1.5368.

d. To g of dry sodium hydrogen sulfate preheated to 220 to 230 is addedunder a vacuum of 100-110 mml-ig within 3 hours 54 g ofl-(p-chlorophenyl)- propanol. The reaction is then distilled 'underabout 14- mml-lg. The distillate is extracted with ether. The etherextract is dried over magnesium sulfate and sodium bicarbonate andevaporated. The residue is fractionated under vacuum to givep-chloro-B-methylstyrene, bp 8082/1 5 mmHg; n 1.5660.

e. To a stirred mixture of 50 g of dry ethylene imine and about 500 mgof metallic sodium is added at room temperature dropwise 33 g ofp-chloro-B-methylstyrene. When the temperature starts to rise afterabout two hours stirring it is kept by outside cooling at about 30.Stirring is continued at about 25 for about 30 minutes after thereaction is completed. Unreacted sodium is removed mechanically and theexcess ethylene is removed in vacuo. The residue is distilled andfractionated in vacuo to give 1-(p-chlorophenyl)-2-(1-aziridinyl)-propan; bp 120-l21/14 mmHg; 11 1.5272.

f. A solution of 39.5 g of l-(p-chlorophenyD-Z-(laziridinyl)-propan in100 ml of ethanol is added at 5 within 15 minutes to 150 ml of asaturated ethanolic hydrogen chloride solution. The solution isevaporated until crystallization occurs, then cooled, whereupon thecrystals are filtered off. They are recrystallized from ethanol to givel-(p-chlorophenyl)-2-(2- chloroethylamino)-propan hydrochloride; mp189-19 1.

EXAMPLE 3 Two hundred and fifty g of 7-chloro-2,3,4,5-

tetrahydro-lH-S-benzazepine hydrochloride are mixed with 175.80 g oflactose and 169.70 g of potato starch, the mixture is moistened with analcoholic solution of 10 g of stearic acid and granulated through asieve. After drying, 160 g of potato starch, 200 g of talcum, 2.50 g ofmagnesium stearate and 32 g of colloidal silicon dioxide are mixed inand the mixture is pressed into 10,000 tablets each weighing mg andcontaining 25 mg of active substance. If desired, the tablets can begrooved for better adaptation of the dosage.

Tablets each containing 25 mg of 2,-methyl-7-chloro-2,3,4,5-tetrahydro-ll-l-3-benzazepine hydrochloride are prepared inanalogous manner.

EXAMPLE 4 A granulate is produced from 250 g of 7-chloro-2,3,4,5-tetrahydro-1l-l-3-benzazepine hydrochloride, 175.90 g of lactoseand the alcoholic solution of 10 g of stearic acid. After drying, thegranulate is mixed with 56.60 g of colloidal silicon dioxide, 165 g oftalcum, 20 g of potato starch and 2.50 g of magnesium stearate and themixture is pressed into 10,000 dragee cores. These are then coated witha concentrated syrup made from 502.28 g of crystallized saccharose, 6 gof shellac, 10 g of gum arabic, 0.22 g of dyestuff and 1.5 g of titaniumdioxide and dried. The dragees obtained each weigh mg and contain 25 mgof active substance.

Dragees each containing 25 g of 2-methyl-7-chloro-2,3,4,5-tetrahydro-ll-l-3-benzazepine hydrochloride are prepared inanalogous manner.

What is claimed is:

1. A method of producing an anorexigenic effect in a mammal sufferingfrom obesity comprising administering to that mammal an anorexigenicallyeffective amount of a compound of the formula wherein R is hydrogen ormethyl or a pharmaceutically acceptable acid addition salt thereof.

2. A method according to claim 1 wherein said compound is 7-chloro-2,3,4,5-tetrahydro-l 1-1-3- benzazepine.

3. A method according to claim 1 wherein said compound is2-methyl-7-chloro-2,3,4,5-tetrahydro-11-1-3- benzazepine.

4. A therapeutic composition consisting essentially of ananorexigenically effective amount of a compound of the formula wherein Ris hydrogen or methyl or a pharmaceutically acceptable acid additionsalt thereof and a solid pulverulent pharmaceutical carrier.

5. A therapeutic composition according to claim 4 wherein said compoundis 7-chloro-2,3,4,5-tetrahydrolH-3-benzazepine.

6. A therapeutic composition according to claim 4 wherein said compoundis 2-methyl-7-chloro-2,3,4,5- tetrahydro-l1-l-3-benzazepine.

1. A method of producing an anorexigenic effect in a mammal sufferingfrom obesity comprising administering to that mammal an anorexigenicallyeffective amount of a compound of the formula wherein R is hydrogen ormethyl or a pharmaceutically acceptable acid addition salt thereof.
 2. Amethod according to claim 1 wherein said compound is7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine.
 3. A method according toclaim 1 wherein said compound is2-methyl-7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine.
 4. A therapeuticcomposition consisting essentially of an anorexigenically effectiveamount of a compound of the formula wherein R is hydrogen or methyl or apharmaceutically acceptable acid addition salt thereof and a solidpulverulent pharmaceutical carrier.
 5. A therapeutic compositionaccording to claim 4 wherein said compound is7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepine.